Cardiovascular Outcomes Underreported in Cancer Trials

In what is sure to raise red flags for many cardiologists, a recent review of phase 2 and phase 3 trials supporting FDA approval of cancer drugs between 1998 and 2018 found nearly 40% of trials did not report any cardiovascular disease (CVD) events.

Performed by investigators from the Ohio State University Medical Center, the review examined more than 180 clinical trials found only 62.4% reported incidence of major adverse cardiovascular events (MACE)—suggesting physicians should use caution when interpreting the cardiotoxicity risk associated with some therapies.

With cardiovascular disease appearing to rise concurrently with a rise in anticancer drug approvals beginning in the late 1990s, investigators sought to assess whether CVD events were routinely and consistently reported in pivotal clinical trials. Using the Drugs@FDA database, the investigators identified all anticancer therapies that received approval between 1998 and 2018.

For the analysis, the primary outcome was the incidence of MACE, which included myocardial infarction, stroke, congestive heart failure, atrial fibrillation, coronary revascularization, or cardiovascular death among trial participants. The report of any CVD event by trial participants was used as the secondary outcome measure.

From the Drugs@FDA database, 189 trials examining 123 drugs were identified for inclusion. From these trials, a cohort of 97,365 patients was identified—giving investigators access to 148,138 person-years of follow-up data. Of the 97,365 patients identified for inclusion, 57,978 were part of their respective trial’s intervention arm.

The median age of study participants was 61 years old. The median size of trials included ranged from 100 to 499 participants and biologics, targeted, and immune-based therapies made up 72.5% of drugs approved during the study period.

In 81% of the trials, common terminology criteria for adverse event was used for CVD threshold definitions. Additionally, 51.3% of trials did not report MACE—including 37.6% who did not report any CVD events during the follow-up.

During the 148,138 person-years of follow-up, a total of 1148 MACE events were reported. In trials that reported MACE, 792 were noted within the intervention arms compared to 356 in the control arms of the studies (P <.01). When examining the 4739 total reported CVD events, 3142 occurred in the intervention arms compared to 1597 in the control arms (P <.01).

When examining the most commonly reported types of CVD events reported in cancer trials, CVD death (n=56) was the most commonly reported event followed by thromboembolic disease (n=34), uncontrolled hypertension (n=30), heart failure (n=30), cerebrovascular accident (n=26), other CVD (n=17), and acute coronary syndrome (n=13).

In assessments of reporting by therapeutic class, investigators found reporting prevalence ranged from 76% of trials for targeted therapies to just 39% of trials for chemotherapy drugs. Hormonal therapies reported CVD 50% of the time and biologic or immunotherapy trials reported CVD events 63% of the time.

Additionally, 24 of 64 trials where patients with CVD at baseline were excluded from participation did not report MACE. During these trials, 269 MACE events occurred from a total of 2590 CVD events from 49,660 yeas of trail patient follow-up. This correlates to an overall weight average reported incidence rate of 716 per 100,000 person-years in the intervention arms for MACE events compared to 1408 among similar-aged non-cancer subjects, which investigators noted translate to a risk difference of 866. Investigators pointed out there was no association between drug efficacy and reporting CVD events (HR 0.68 versus HR 0.67; P = .22).

In a summary published on the American College of Cardiology website, Salim Hayek, MD, a cardiologist at the University of Michigan Medicine, writes the study’s results and apparent lack of reporting in clinical trials are cause for concern and warrant additional research to more accurately assess adverse cardiovascular impacts of new cancer therapies.

“As CVD is increasingly being recognized as a major barrier for the long-term survival and quality of life of patients with cancer, the markedly lower rate of reported CVD events in cancer trials compared to noncancer patients gives one pause,” Hayek wrote.

This study, “Reporting of Cardiovascular Events in Clinical Trials Supporting FDA Approval of Contemporary Cancer Therapies,” in JACC.